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Ivermectin cytotoxic t(4:14) Myeloma

Multiple Myeloma Stages
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According to the research linked below, Ivermectin is cytotoxic to t(4:14) myeloma. This is welcome news to any newly diagnosed MM patient who has been diagnosed as being high risk due to the 4:14 translocation.

Further, Ivermectin has been shown to enhance the efficacy of velcade/bortezomib.


Which chemotherapy regimens have been shown to be cytotoxic to the 4:14 gene translocation in myeloma?

  1. Bortezomib-Based Regimens: Bortezomib (Velcade) has shown significant efficacy in patients with t(4;14) myeloma. Studies suggest that regimens incorporating bortezomib, such as VTD (bortezomib, thalidomide, dexamethasone) or VRd (bortezomib, lenalidomide, dexamethasone), can overcome the poor prognosis associated with this translocation.
  2. Carfilzomib-Based Regimens: Carfilzomib, another proteasome inhibitor, has also been effective in this subgroup. Regimens like KRd (carfilzomib, lenalidomide, dexamethasone) have been used with success in t(4;14) myeloma.
  3. Daratumumab: As a monoclonal antibody targeting CD38, daratumumab has been effective in various myeloma subtypes, including those with t(4;14). When combined with other agents like bortezomib or lenalidomide, it enhances the cytotoxic effects.
  4. Lenalidomide-Based Regimens: Although lenalidomide (Revlimid) is not as specifically targeted as proteasome inhibitors for t(4;14), it is frequently included in combination therapies that have shown effectiveness in this subgroup, particularly when used with bortezomib or carfilzomib.
  5. Cyclophosphamide and Doxorubicin-Based Regimens: Traditional chemotherapy agents like cyclophosphamide and doxorubicin are often included in combination regimens for myeloma. They provide cytotoxic effects and are part of regimens like CyBorD (cyclophosphamide, bortezomib, dexamethasone), which have been used in treating t(4;14) myeloma.

As a MM survivor, I am often conflicted when I research and write about a therapy that is not FDA approved yet shows efficacy in treating MM. Especially a gene mutation that puts the MM patient at high-risk.

I guess what I’m saying is that MM patients who take Ivermectin as a MM therapy must understand the risks involved by using a therapy that is not FDA approved for MM.

If you have any questions about MM, email me at David.PeopleBeatingCancer@gmail.com

David Emerson

  • MM Survivor
  • MM Cancer Coach
  • Director PeopleBeatingCancer

Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

“Purpose  Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters…

Results- We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients.
Conclusion- Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction…”

Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma

“BACKGROUND Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets…

RESULTS In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely:

  • cytokine receptor interactions,
  • nuclear factor (NF)-κB signaling pathway,
  • lipid metabolism,
  • atherosclerosis,
  • and Hippo signaling pathway,

were identified. Ten hub genes (cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM.

In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb. Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.

Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells…

Ivermectin induces apoptosis in t(4;14) MM cells Drug-induced apoptosis is the primary mechanism underlying cancer cell death[18]. To assess this, we analyzed the expression of the pro- and anti-apoptotic proteins BAX and BCL2, respectively, after treatment and further inspected the BAX/BCL2 ratio.

We observed that ivermectin induced apoptosis in t(4;14) MM cells, as evidenced by the upregulation of pro-apoptotic protein BAX and a decrease in anti-apoptotic protein BCL2 levels (Figure 3C). The BAX/BCL2 ratio significantly increased (Figure 3D), and the intrinsic mitochondrial apoptotic pathway was activated, as indicated by elevated caspase-9, caspase-3, downstream effector caspase-3, and PARP expression levels (Figure 3E and F). Annexin V-FITC/propidium iodide staining revealed a substantial increase in the proportion of apoptotic t(4;14) MM cells after ivermectin treatment compared with that of the control (Figure 3G and H), highlighting that the suppressive effect of ivermectin on t(4; 14) MM cells was associated with apoptosis…”

 

 

 

 

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